1825 Review www.expert-reviews.com ISSN 1473-7140 © 2010 Expert Reviews Ltd 10.1586/ERA.10.160 For over 30 years, tamoxifen – a selective estrogen receptor modulator (SERM) – was the agent of choice for the treatment of hormone-responsive early and advanced breast cancer (BC). SERMs are synthetic molecules that bind to the estro- gen receptor, thereby modulating its transcrip- tional capabilities [1] . Despite its effectiveness, the drawbacks of tamoxifen include its partial agonist activity, the eventual resistance of many tumors to the drug, poor compliance and serious adverse events (AEs) such as endometrial cancer and thromboembolic disease [2–4] . Therefore, alternative treatments are warranted. The third-generation aromatase inhibitors (AIs) developed in the early 1990s include two nonsteroidal triazole derivatives (anastrozole [Arimidex ® ; AstraZeneca, London, UK] and letrozole [Femara ® ; Novartis International AG, Basel, Switzerland]), and a steroidal androstene- dione derivative (exemestane [Aromasin ® ; Pfizer Inc., NY, USA]). Anastrozole and letrozole bind reversibly to the aromatase active site [5] while exemestane is an irreversible inhibitor [6] . These AIs function by inhibiting aromatase, a cyto- chrome P450 enzyme [7–9] , thereby effectively suppressing estrogen synthesis [10,11] . Clinically, AIs are used for the treatment of women with BC in whom ovarian function has ceased owing to menopause, or ovarian ablation from surgery, radiation therapy or cytotoxic chemotherapy [12] . Impact of AIs on micrometastases A primary goal of systemic adjuvant therapy for BC is to eradicate micrometastases, thereby con- trolling the risk of recurrence following surgery and improving long-term survival [13] . In a study of 3614 postmenopausal (PM) women with endocrine receptor (ER)-positive operable BC, an early peak of distant recurrence was observed despite treatment with tamoxifen [14] . As a con- sequence, there is a need for therapies capable of reducing this early peak in order to improve survival. Evidence suggests the superiority of AIs over tamoxifen with respect to alleviating the early peak of distant metastases (DM) in BC [15] . Overview, clinical trial data of third-generation AIs The use of AIs as adjuvant treatment for PM women has been examined in a number of large Phase III randomized clinical trials, each employing various treatment strategies of AIs versus tamoxifen for 5 years: upfront, switching, sequencing and extended adjuvant. Henning T Mouridsen †1 , Per Lønning 2 , Matthias W Beckmann 3 , Kimberly Blackwell 4 , Julie Doughty 5 , Joseph Gligorov 6 , Antonio Llombart-Cussac 7 , Andre Robidoux 8 , Beat Thürlimann 9 and Michael Gnant 10 1 Danish Breast Cancer Cooperative Group, Rigshospitalet, Department of Oncology 2501, Blegdamsvej 9, Kobenhavn O 2100, Denmark 2 Department of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway 3 Frauenklinik, Universitatsklinikum Erlangen, Erlangen, Germany 4 Medical Oncology Department, Duke University Medical Center, Durham, NC, USA 5 Western Infirmary Glasgow, Glasgow, Scotland, UK 6 Medical Oncology Department, Tenon Hospital, Paris, France 7 Medical Oncology Department, Hospital Universitario Arnau Vilanova, Lleida, Spain 8 Department of Surgery, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada 9 Breast Center Kantonsspital St Gallen, St Gallen, Switzerland 10 Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria † Author for correspondence: Tel.: +45 3538 6530 Fax: +45 3545 6966 henning.mouridsen@rh.regionh.dk Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer. KEYWORDS:฀anticancer฀•฀aromatase฀inhibitors฀•฀bisphosphonates฀•฀breast฀cancer฀•฀distant฀metastases Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer Expert Rev. Anticancer Ther. 10(11), 1825–1836 (2010) For reprint orders, please contact reprints@expert-reviews.com